Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals

Respir Res. 2012 Aug 6;13(1):67. doi: 10.1186/1465-9921-13-67.


Background: Mutations in ATP-binding-cassette-member A3 (ABCA3) are related to severe chronic lung disease in neonates and children, but frequency of chronic lung disease due to ABCA3 mutations in the general population is unknown. We tested the hypothesis that individuals heterozygous for ABCA3 mutations have reduced lung function and increased risk of COPD in the general population.

Methods: We screened 760 individuals with extreme pulmonary phenotypes and identified three novel (H86Y, A320T, A1086D) and four previously described mutations (E292V, P766S, S1262G, R1474W) in the ABCA3 gene. We genotyped the entire Copenhagen City Heart study (n = 10,604) to assess the clinical importance of these mutations. To validate our findings we genotyped an additional 54,395 individuals from the Copenhagen General Population Study.

Results: In the Copenhagen City Heart Study individuals heterozygous for E292V had 5% reduced FEV₁ % predicted compared with noncarriers (t-test: p = 0.008), and an increased odds ratio for COPD of 1.9 (95% CI: 1.1-3.1). In contrast, the A1086D mutation was associated with increased FEVFEV₁ % predicted (p = 0.03). None of the other ABCA3 mutations associated with lung function or COPD risk in the Copenhagen City Heart Study. In the larger Copenhagen General Population Study, and in the two studies combined, E292V heterozygotes did not have reduced lung function or increased risk of COPD (p = 0.11-0.98), while this was the case for the positive controls, surfactant protein-B 121ins2 heterozygotes and α₁-antitrypsin ZZ homozygotes.

Conclusion: Our results indicate that partially reduced ABCA3 activity due to E292V is not a major risk factor for reduced lung function and COPD in the general population. This is an important finding as 1.3% in the Danish population has partially reduced ABCA3 function due to E292V.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • Adult
  • Aged
  • Amino Acid Substitution
  • Denmark
  • Female
  • Heterozygote
  • Humans
  • Lung / physiopathology*
  • Male
  • Middle Aged
  • Mutation
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Pulmonary Disease, Chronic Obstructive / physiopathology*
  • Respiratory Function Tests


  • ABCA3 protein, human
  • ATP-Binding Cassette Transporters